The discussion that follows is intended solely as background information to assist in the understanding of this invention; nothing in this section is intended to be, nor is it to be construed as, prior art to the invention.
The androgen receptor (AR) belongs to the family of nuclear hormone receptors. Nuclear hormone receptors define a superfamily of ligand activated transcription factors. Members of this family are characterized by a number of modular domains: a zinc finger DNA binding domain (DBD), which triggers the interaction of the receptor with specific response elements at the DNA site, a ligand binding domain (LBD) adjacent to the DBD, and two transcriptional activation domains AF-1 and AF-2, which are ligand-independent and ligand-dependent, respectively. Upon ligand binding to the receptor, a conformational change occurs within the LBD bringing the AF-2 domain in closer proximity and allowing for the recruitment of co-activators. Co-activators create a physical interaction between the nuclear hormone receptor and components of the transcriptional machinery, establishing transcriptional modulation of target genes.
The steroid sex hormones testosterone and the more potent dihydroxy testosterone (DHT) represent the AR endogenous ligands. Through activation of the receptor, these “male sex hormones” modulate a number of physiological processes most notably primary and secondary male characteristics.
Clinical situations in which levels of plasma testosterone are decreased, also known as hypogonadism, have been extensively studied. For instance, children suffering from such a condition exhibit a total absence of pubertal development. Delay in puberty leads to psychological problems, secondary to short stature and/or delay in the acquisition of secondary sexual characteristics and the reduction of bone mass. Moreover, several epidemiological studies have confirmed that plasma testosterone levels gradually decrease with aging. On average a quarter of men in their sixties display clinical hypogonadism. This condition is even more prevalent among male octogenarians where 50-80% of men in this age group clinically qualify for hypogonadism. Decreased testosterone plasma levels are also seen in aging women. Age-related hypogonadism is associated with an obvious impairment in the quality of life from physical manifestations (muscle, bone density loss) to psychological problems (mood disorders, cognition, decreased libido). This condition is referred to as “male menopause” or “andropause”.
Current therapies rely on the use of testosterone and testosterone analogs. They are the treatment of choice in delayed male puberty, male fertility as well as endometriosis. Because of the strong anabolic effects of this class of steroid hormones, they have been therapeutically approved for restoring skeletal muscle mass in patients suffering from burns. A number of placebo controlled clinical studies have reported a therapeutic benefit to androgen agonism in aging men. In particular, reports have emerged demonstrating the benefit of testosterone replacement therapy in improving a number of aspects of age related hypogonadism such as bone density, anabolism, libido, mood disorders (lack of vigor, well being) and cognition. In the ophthalmologic arena, dry eye is also amenable to treatment with testosterone or testosterone analogs. More recent studies have highlighted a correlation between decreasing testosterone levels and increased incidence of Alzheimer's disease.
Since oral preparations of testosterone and testosterone analogs are ineffective due to enhanced first-pass metabolism and hepatotoxicity, intramuscular injectable forms of long-acting esters have constituted the basis of testosterone replacement therapy. However, the large fluctuations of serum testosterone levels induced by these preparations cause unsatisfactory shifts of mood and sexual function in some men; because of the frequent injections required, this delivery mode is thus far from being ideal. In contrast, transdermal testosterone patches display more favorable pharmacokinetic properties and have proven to be an effective mode of delivery. Nevertheless, testosterone patch systems (especially scrotal patches) are hampered by the high rate of skin irritations. Recently, testosterone gels have gained approval. Gels are applied once daily on the skin in quantities large enough to deliver sufficient amounts of testosterone to restore normal hormonal values and correct the signs and symptoms of hypogonadism. However while being very effective, this mode of application raises matters of adequate and consistent delivery.
Steroidal AR ligands, however, are plagued by undesirable adverse side effects, for instance prostate enlargement, acne, hirsutism, virilization and masculinisation. Furthermore, the androgenic property of testosterone and its analogs are thought to constitute a enhanced risk of prostate cancer. Thus, a search has been initiated for non-steroidal compounds that can modulate the activity of AR ligands; such compounds are referred to as Selective Androgen Receptor Modulators or SARMs. It is expected that this class of compounds will in general demonstrate better pharmacokinetic and specificity profiles than current steroidal therapies. In particular, non-steroidal SARMs are expected to lack androgenic properties. Second generation SARMs are expected contribute additional therapeutic benefits by displaying positive anabolic properties and antagonistic androgenic components. Another desirable feature of SARMs is expected to be their significant bioavailability.